Highly Efficient and Long-Lasting Chemiluminescence-Functionalized Nanohydrogel for Imaging-Guided Precise Piperlongumine Chemotherapy

A major challenge for imaging-guided precise chemotherapy remains the ability to track the in situ real-time variation of the reactive oxygen species (ROS) level during treatment with prooxidation antitumor drugs. Chemiluminescence (CL) is widely used as an <i>in vivo</i> imaging tool with an excellent signal-to-noise ratio and high biological safety. However, suffering from flash-type and poor water solubility, most of the reported CL probes for ROS detection are unsuitable for in vivo long-term tracking. Herein, we designed a water-soluble CL nanohydrogel (L-012/Co²⁺@NGs) by cross-linking of vinyl-derived β-cyclodextrin monomer (MAH-β-CD) and loaded with luminol analog L-012 and cobalt ions (Co²⁺). <i>In vitro</i> studies reveal that L-012/Co²⁺@NGs exhibit long-lasting CL emission (up to 4 h) due to the slow diffusion of hydrogen peroxide in the nanohydrogel. High catalytic efficiency from the accelerated reduction of Co³⁺ to Co²⁺ through Tris and chelation of Co²⁺, as well as protection of the β-CD cavity against the active intermediate of L-012, enables L-012/Co²⁺@NGs to exhibit a 722-fold CL signal turn-on ratio and a nanomolar limit of detection (8.9 nmol/L). Piperlongumine (PL) was selected as a model of prooxidation drugs. The long-term and highly efficient CL strategy was designed for monitoring the local dynamic changes of ROS in PL-treated tumor-bearing mice for 150 min. The CL signal increased over time until reaching its maximum with a ∼6-fold increase at 15 min and then decreased slowly. The CL-functionalized nanohydrogel platform with good biocompatibility offers a great opportunity for imaging-guided precise tumor chemotherapy of PL and other prooxidation antitumor drugs.